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Inhibitory Activities of Trichostatin A in U87 Glioblastoma Cells and Tumorsphere-Derived Cells

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Abstract

Epigenetic alterations have been increasingly implicated in glioblastoma (GBM) pathogenesis, and epigenetic modulators including histone deacetylase inhibitors (HDACis) have been investigated as candidate therapies. GBMs are proposed to contain a subpopulation of glioblastoma stem cells (GSCs) that sustain tumor progression and therapeutic resistance and can form tumorspheres in culture. Here, we investigate the effects of the HDACi trichostatin A (TSA) in U87 GBM cultures and tumorsphere-derived cells. Using approaches that include a novel method to measure tumorsphere sizes and the area covered by spheres in GBM cultures, as well as a nuclear morphometric analysis, we show that TSA reduced proliferation and colony sizes, led to G2/M arrest, induced alterations in nuclear morphology consistent with cell senescence, and increased the protein content of GFAP, but did not affect migration, in cultured human U87 GBM cells. In cells expanded in tumorsphere assays, TSA reduced sphere formation and induced neuron-like morphological changes. The expression of stemness markers in these cells was detected by reverse transcriptase polymerase chain reaction. These findings indicate that HDACis can inhibit proliferation, survival, and tumorsphere formation, and promote differentiation of U87 GBM cells, providing further evidence for the development of HDACis as potential therapeutics against GBM.

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Acknowledgments

This research was supported by the National Council for Scientific and Technological Development (CNPq; grant numbers 303703/2009-1 and 484185/2012-8 to R.R); the National Institute for Translational Medicine (INCT-TM); FAPERGS/CNPq grant number 10/0044-3-PRONEX; the University Hospital Research Fund (FIPE/HCPA); the South American Office for Anticancer Drug Development; and the Rafael Koff Acordi Research Fund, Children’s Cancer Institute (ICI-RS). F.A.S, P.L.C.L., and C.N. are supported by CNPq fellowships.

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  1. Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Felipe de Almeida Sassi, Lílian Caesar, Mariane Jaeger, Carolina Nör, Ana Lucia Abujamra, Gilberto Schwartsmann, Caroline Brunetto de Farias, Algemir Lunardi Brunetto, Patrícia Luciana da Costa Lopez & Rafael Roesler

  2. National Institute for Translational Medicine, Porto Alegre, RS, Brazil

    Felipe de Almeida Sassi, Lílian Caesar, Mariane Jaeger, Carolina Nör, Ana Lucia Abujamra, Gilberto Schwartsmann, Caroline Brunetto de Farias, Algemir Lunardi Brunetto, Patrícia Luciana da Costa Lopez & Rafael Roesler

  3. Children’s Cancer Institute (ICI-RS), Porto Alegre, RS, Brazil

    Lílian Caesar, Ana Lucia Abujamra, Caroline Brunetto de Farias & Algemir Lunardi Brunetto

  4. Department of Internal Medicine, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Gilberto Schwartsmann

  5. Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Rafael Roesler

  6. Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), 90050-170, Porto Alegre, RS, Brazil

    Rafael Roesler

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  1. Felipe de Almeida Sassi
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  2. Lílian Caesar
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  10. Rafael Roesler
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Correspondence to Rafael Roesler.

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Sassi, F.A., Caesar, L., Jaeger, M. et al. Inhibitory Activities of Trichostatin A in U87 Glioblastoma Cells and Tumorsphere-Derived Cells. J Mol Neurosci 54, 27–40 (2014). https://doi.org/10.1007/s12031-014-0241-7

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  • DOI: https://doi.org/10.1007/s12031-014-0241-7

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